Objective To investigate the effect of liquid-liquid phase separation(LLPS)of YTH domain family protein 2(YTHDF2)on the sodium arsenite-induced malignant transformation of skin cells,providing a new intervention target for the prevention and control of sodium arsenite-induced carcinogenesis.Methods The HaCaT cell model of malignant transformation was constructed by continuous treatment with 1 μmol/L sodium arsenite for 22 weeks,including cells with normal YTHDF2 LLPS(YTHDF2-wt)and cells with inhibited YTHDF2 LLPS(YTHDF2-mut).Confocal microscopy was employed to observe and characterize the LLPS droplets formed by YTHDF2 during sodium arsenite-induced malignant transformation of skin cells.Cell proliferation,scratch healing,and colony formation assays were performed to detect malignant phenotypes.Western blotting,quantitative reverse transcription PCR,and immunofluorescence experiments were conducted to examine the effects of YTHDF2 LLPS on the mRNA and protein levels of phosphatase and tensin homolog deleted on chromosome ten(PTEN)during sodium arsenite-induced malignant transformation of skin cells.Results After 4 weeks of sodium arsenite treatment,LLPS droplets of YTHDF2 appeared in YTHDF2-wt cells,and the number of droplets gradually increased as the treatment time was prolonged(F=35.252,P<0.001),while no phase-separated droplets were observed in YTHDF2-mut cells.Compared with YTHDF2-mut cells,YTHDF2-wt cells showed enhanced proliferation at the time points of 48 h(t=3.654,P=0.006)and 72 h(t=5.458,P<0.001)after 22 weeks of sodium arsenite treatment.The scratch healing rate of YTHDF2-wt cells was increased at the 8th(t=12.137,P<0.001)and 22th(t=4.484,P=0.011)weeks of sodium arsenite treatment.The number of colonies formed by YTHDF2-wt cells was higher at the 4th(t=3.365,P=0.027),8th(t=5.580,P=0.005),and 22th(t=3.328,P=0.029)weeks of sodium arsenite treatment.Compared with YTHDF2-mut cells,YTHDF2-wt cells showed down-regulated protein(t=-3.119,P=0.036)and mRNA(t=4.051,P=0.015) levels of PTEN after 22 weeks of sodium arsenite treatment.Immunofluorescence results showed that after 4 weeks of sodium arsenite treatment,YTHDF2 LLPS droplets in YTHDF2-wt cells were localized to stress granules,translation-related membrane-less organelles.Conclusions During sodium arsenite-induced malignant transformation of skin cells,YTHDF2 undergoes LLPS and localizes to stress granules,translation-related membrane-less organelles.YTHDF2 LLPS participates in sodium arsenite-induced malignant transformation of skin cells by down-regulating the mRNA level of the key tumor suppressor PTEN.
Arsenites/toxicity* ; Sodium Compounds/toxicity* ; Humans ; Cell Transformation, Neoplastic/drug effects* ; PTEN Phosphohydrolase/metabolism* ; Cell Proliferation ; Skin/cytology* ; RNA-Binding Proteins ; Skin Neoplasms/chemically induced* ; Cell Line

OBJECTIVE: To establish a SD rat model of vulvar squamous intraepithelial lesions. METHODS: Seventy female SD rats were randomized into 4 groups, namely the blank control group (=10), mechanical irritation group (=10), acetone solution group (=10), and mechanical irritation with DMBA acetone solution group (=40, model group), and the corresponding treatments were administered 3 times a week for 14 weeks. The changes of the vulvar skin of the rats were observed regularly until the 18th week. The expression of mutant p53 (mtp53) and vascular endothelial growth factor (VEGF) proteins were detected using immunohistochemistry and Western blotting, and the expressions of mtp53 and VEGF mRNA were detected with qRT- PCR in the blank control group and model group. RESULTS: No significant differences were found in the morphological or histopathological changes of the skin among the blank control group, mechanical irritation group and acetone solution group. In the model group, low-grade squamous intraepithelial lesions (LSIL) occurred in 28 rats (70%) and high-grade squamous intraepithelial lesions (HSIL) in 11 rats (27.5%) at 14 weeks, with a success rate of 97.5% in inducing vulvar squamous intraepithelial lesions. Compared with the blank control group, the rats in the model group showed significantly increased expressions of mtp53 and VEGF at both the protein level ( < 0.05) and the mRNA level ( < 0.05). CONCLUSIONS DMBA in acetone solution combined with mechanical irritation can induce vulvar squamous intraepithelial lesions in female SD rats.
9,10-Dimethyl-1,2-benzanthracene ; Acetone ; Animals ; Blotting, Western ; Carcinogens ; Disease Models, Animal ; Female ; Friction ; Immunohistochemistry ; Precancerous Conditions ; chemically induced ; metabolism ; pathology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Skin ; pathology ; Solvents ; Tumor Suppressor Protein p53 ; metabolism ; Vascular Endothelial Growth Factor A ; metabolism ; Vulvar Neoplasms ; chemically induced ; metabolism ; pathology

OBJECTIVETo study the curative effect of Zhiyang Pingfu Liquid (ZPL) in treating epidermal growth factor receptor inhibitors (EGFRIs) associated adverse reactions of the skin.

METHODSAll 54 patients with pathologically confirmed malignant tumor had EGFRIs induced adverse reactions of the skin to various degrees. ZPL was externally applied for them all, once or twice per day, 14 days consisting of one therapeutic course. Changes of adverse skin reactions, time for symptoms relief, adverse skin reaction types suitable for ZPL were observed before and after treatment.

RESULTSEGFRIs associated skin adverse reactions were improved to various degrees after they used ZPL. The shortest symptoms relief time was 1 day while the longest was 12 days, with an average of 6.93 days and the median time 7 days. Compared with before treatment, itching, rash/scaling, acne/acneform eruptions were obviously improved (P < 0.05).

CONCLUSIONZPL could alleviate EGFRls associated adverse skin reactions, especially showed better effect on itching, rash/scaling, acne/acneform eruptions.

Antineoplastic Agents ; adverse effects ; Biomedical Research ; Drugs, Chinese Herbal ; administration & dosage ; therapeutic use ; Exanthema ; chemically induced ; Humans ; Neoplasms ; drug therapy ; Pruritus ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; Skin ; drug effects ; Skin Diseases ; drug therapy

Animals ; Carcinoma, Squamous Cell ; genetics ; Colorectal Neoplasms ; genetics ; metabolism ; Enzyme Activation ; Esophageal Neoplasms ; genetics ; Genome-Wide Association Study ; Head and Neck Neoplasms ; genetics ; Humans ; Neoplasms ; chemically induced ; enzymology ; genetics ; Phosphoinositide Phospholipase C ; chemistry ; genetics ; metabolism ; physiology ; Signal Transduction ; Skin Neoplasms ; chemically induced ; enzymology ; Stomach Neoplasms ; genetics ; Urinary Bladder Neoplasms ; metabolism ; pathology ; ras Proteins ; metabolism

The increasing incidence and mortality associated with advanced stages of melanoma are cause for concern. Few treatment options are available for advanced melanoma and the 5-year survival rate is less than 15%. Targeted therapies may revolutionize melanoma treatment by providing less toxic and more effective strategies. However, maximizing effectiveness requires further understanding of the molecular alterations that drive tumor formation, progression, and maintenance, as well as elucidating the mechanisms of resistance. Several different genetic alterations identified in human melanoma have been recapitulated in mice. This review outlines recent progress made in the development of mouse models of melanoma and summarizes what these findings reveal about the human disease. We begin with a discussion of traditional models and conclude with the recently developed RCAS/TVA somatic cell gene delivery mouse model of melanoma.
9,10-Dimethyl-1,2-benzanthracene ; Animals ; Avian Leukosis Virus ; genetics ; Avian Proteins ; genetics ; metabolism ; Cell Line, Tumor ; Disease Models, Animal ; Gene Transfer Techniques ; Genetic Vectors ; genetics ; Humans ; Melanocytes ; metabolism ; Melanoma ; genetics ; pathology ; Melanoma, Experimental ; chemically induced ; genetics ; Mice ; Mice, Transgenic ; Neoplasm Transplantation ; Receptors, Virus ; genetics ; metabolism ; Skin Neoplasms ; genetics ; pathology ; Tetradecanoylphorbol Acetate ; Transgenes

OBJECTIVETo evaluate the efficacy, side effects and toxicity of imatinib mesylate in the treatment of patients with locally advanced and/or metastatic dermatofibrosarcoma protuberans (DFSP).

METHODSTwenty-four cases of advanced DFSP diagnosed by pathology and treated in our hospital from Nov. 2004 to Oct. 2009 were included in this study. The patients were treated with imatinib mesylate (dosage: 400 mg, po, qd) and carefully observed for treatment efficacy, side effects and survival time. There were 2 patients taking the drug as second line therapy, and other 22 patients as third or more than third line therapy.

RESULTSThe 24 patients were evaluable for the efficacy. There were 8 patients (33.3%) with CR, 10 pts (41.7%) PR, 2 patients (8.3%) SD, and 4 patients (16.7%) PD. The disease control rate (DCR = CR+PR+SD) was 83.3%. The median response time in 18 cases with CR and PR was 5.6 months. The median survival time in 20 cases with disease control was 30 months, however, that in nonresponse (PD) cases was only 10 months. Side reactions related to imatinib mesylate included nausea and vomiting (20.8%), neutropenia (12.5%), and edema (8.3%).

CONCLUSIONSOur results are consistent with previous reports in the literature. Imatinib is a safe and effective moleucular target drug used for Chinese. Only mild adverse reactions occur in the treated patients. It is worth using imatinib in the treatment of advanced DFSP patients.

Adult ; Aged ; Antineoplastic Agents ; adverse effects ; therapeutic use ; Benzamides ; Dermatofibrosarcoma ; drug therapy ; metabolism ; pathology ; Edema ; chemically induced ; Female ; Follow-Up Studies ; Humans ; Imatinib Mesylate ; Male ; Middle Aged ; Nausea ; chemically induced ; Neoplasm Metastasis ; Neoplasm Staging ; Neutropenia ; chemically induced ; Piperazines ; adverse effects ; therapeutic use ; Proto-Oncogene Proteins c-kit ; metabolism ; Pyrimidines ; adverse effects ; therapeutic use ; Receptors, Platelet-Derived Growth Factor ; metabolism ; Remission Induction ; Skin Neoplasms ; drug therapy ; metabolism ; pathology ; Survival Rate ; Vomiting ; chemically induced

A 31-yr-old man with abdominal pain was diagnosed with a pancreatic endocrine tumor and multiple hepatic metastases. Despite optimal treatment with interferon alpha, a somatostatin analog, local therapy with high-intensity focused ultrasound ablation for multiple hepatic metastases, and multiple lines of chemotherapy with etoposide/cisplatin combination chemotherapy and gemcitabine monotherapy, the tumor progressed. As few chemotherapeutic options were available for him, sorafenib (800 mg/day, daily) was administered as a salvage regimen. Sorafenib was continued despite two episodes of grade 3 skin toxicity; it delayed tumor progression compared to the previous immunotherapy and chemotherapy. Serial computed tomography scans showed that the primary and metastatic tumors were stable. Thirteen months after beginning targeted therapy, and up to the time of this report, the patient is well without disease progression. We suggest that sorafenib is effective against pancreatic endocrine tumors.
Adult ; Antineoplastic Agents/adverse effects/*therapeutic use ; Benzenesulfonates/adverse effects/*therapeutic use ; Humans ; Liver Neoplasms/drug therapy/pathology/secondary ; Male ; Neuroendocrine Tumors/*diagnosis/drug therapy/pathology ; Pancreatic Neoplasms/*diagnosis/drug therapy/pathology ; Pyridines/adverse effects/*therapeutic use ; Salvage Therapy ; Skin Diseases/chemically induced ; Tomography, X-Ray Computed

OBJECTIVETo evaluate the efficacy and analyze the prognostic factors of sorafenib treatment in patient with unresectable primary hepatocellular carcinoma (HCC).

METHODSDuring the period from December 2005 to March 2009, 50 patients with unresectable primary HCC of Child-Pugh status A were treated with sorafenib (400 mg, Bid). The tumor response was evaluated with CT or MRI imaging every 6 - 8 weeks according to the RECIST criteria. The overall survival (OS) and time to progression (TTP) were defined as the time from administration of sorafenib to the death or the last follow up and were evaluated by Kaplan-Meier method.

RESULTSThere was no PR or CR, but 28 patients (56.0%) achieved stable disease. The median follow up time was 15 months with a median OS of 14 months and median TTP of 4 months. The common adverse events were dermal reaction (68.0%, 34/50), diarrhea (52.0%, 26/50), hypertension (4.0%, 2/50), hair loss (14.0%, 7/50), myelosuppression (16.0%, 8/50), and liver dysfunction (20.0%, 10/50). However, most of the drug-related adverse events were grade I-II and reversible. The patients with lower tumor burden and without distant metastasis had better prognosis.

CONCLUSIONSoafenib is effective for unresectable primary HCC with tolerable toxicity. Tumor stage is a predominant prognostic factor.

Adult ; Aged ; Alopecia ; chemically induced ; Antineoplastic Agents ; adverse effects ; therapeutic use ; Benzenesulfonates ; adverse effects ; therapeutic use ; Carcinoma, Hepatocellular ; drug therapy ; Chemoembolization, Therapeutic ; methods ; Diarrhea ; chemically induced ; Disease Progression ; Follow-Up Studies ; Humans ; Hypertension ; chemically induced ; Liver Neoplasms ; drug therapy ; Male ; Middle Aged ; Neoplasm Staging ; Niacinamide ; analogs & derivatives ; Phenylurea Compounds ; Pyridines ; adverse effects ; therapeutic use ; Skin Diseases ; chemically induced ; Survival Rate

OBJECTIVECalcium Glucarate (Cag), Ca salt of D-glucaric acid is a naturally occurring non-toxic compound present in fruits, vegetables and seeds of some plants, and suppress tumor growth in different models. Due to lack of knowledge about its mode of action its uses are limited in cancer chemotherapy thus the objective of the study was to study the mechanism of action of Cag on mouse skin tumorigenesis.

METHODSWe have estimated effect of Cag on DMBA induced mouse skin tumor development following complete carcinogenesis protocol. We measured, epidermal transglutaminase activity (TG), a marker of cell differentiation after DMBA and/or Cag treatment and [3H] thymidine incorporation into DNA as a marker for cell proliferation.

RESULTSTopical application of Cag suppressed the DMBA induced mouse skin tumor development. Topical application of Cag significantly modifies the critical events of proliferation and differentiation TG activity was found to be reduced after DMBA treatment. Reduction of the TG activity was dependent on the dose of DMBA and duration of DMBA exposure. Topical application of Cag significantly alleviated DMBA induced inhibition of TG. DMBA also caused stimulation of DNA synthesis in epidermis, which was inhibited by Cag.

CONCLUSIONCag inhibits DMBA induced mouse skin tumor development. Since stimulation of DNA synthesis reflects proliferation and induction of TG represents differentiation, the antitumorigenic effect of Cag is considered to be possibly due to stimulation of differentiation and suppression of proliferation.

9,10-Dimethyl-1,2-benzanthracene ; toxicity ; Administration, Topical ; Animals ; Anticarcinogenic Agents ; therapeutic use ; Carcinogens ; toxicity ; Cell Division ; drug effects ; DNA ; biosynthesis ; Enzyme Inhibitors ; toxicity ; Female ; Glucaric Acid ; therapeutic use ; Mice ; Skin Neoplasms ; chemically induced ; enzymology ; prevention & control ; Thymidine ; metabolism ; Transglutaminases ; metabolism

The incidence of tumor and the time of expression, cellular localization and the molecular weight of tumor associated proteins of rat skin tumor induced by 7,12-dimethylbenz[a]anthracene (DMBA) with or without 12-O-tetradecanoyl-phorbol-13-acetate (TPA) were studied. The time of the development of skin tumors in 0.1% DMBA-TPA treated rats was significantly shorter than that in rats which were treated with DMBA alone. In the complete carcinogenesis case, papillomas developed more slowly and were less common and also squamous cell carcinomas appeared much later. From the analysis of the proteins of each experimental group by SDS-PAGE and two dimensional gel electrophoresis, at least three tumor associated proteins were identified (54kd, pl = 5.66; 27kd, pl = 5.85; 11kd, pl = 4.90). Also these proteins were found in rat dorsal skin from 14 days gestation to 21 days postpartum, and disappeared after 28 days. In conclusions, two stage skin carcinogenesis could be successfully demonstrated in Sprague-Dawley rats and abnormal proteins were produced in DMBA or DMBA-TPA induced skin tumor. The tumor associated proteins of skin tumor induced by DMBA or DMBA-TPA were appeared at the late initiation stage or early promotion stage, and they were localized in plasma membrane and were glycoproteins that are thought to be related to the epidermal differentiation process.
9,10-Dimethyl-1,2-benzanthracene ; Animal ; Antigens, Surface/*analysis ; Carcinoma, Squamous Cell/*analysis/chemically induced/pathology ; Cell Membrane/metabolism ; Comparative Study ; Glycoproteins/analysis ; Membrane Proteins/*analysis ; Papilloma/*analysis/chemically induced/pathology ; Rats ; Rats, Inbred Strains ; Skin Neoplasms/*analysis/chemically induced/pathology ; Support, Non-U.S. Gov't ; Tetradecanoylphorbol Acetate